Oxypurin and process of making same.



UNITED STATES PATENT OFFICE,

EMIL FISCHER, OF BERLIN, GERMANY, ASSIGNOR T0 0. F. BOEHRINGER & SOEHNE, OF WALDHOF, GERMANY.

OXYPURIN AND PROCESS OF MAKING SAME.

SPECIFICATION forming part of Letters Patent No. 631 ,708, dated August 22, 1899. Application filed a y 31,1898. Serial N0. 668.646. (Specimens) To all whom it may concern:

Be it known that I, EMIL FISCHER, a citizen of the Empire of Germany, residing at Berlin, in the Empire of Germany, have invented certain new and useful Improvements in the Manufacture of Oxypnrins and their Derivatives; and I do hereby declare the following to be a full, clear, and exact description of the invention, such as will enable others skilled in the art to which it appertains to make and use the same.

The present invention relates to the preparation of oxypurins and their alkyl derivatives, and particularly to the production of a series of bodies starting from trichloropurin,a compound which is described in Letters Patent of the United States No. 598,502, dated February 8, 1898.

The present invention has for its specific object the preparation of xanthin, synthetically, from trichloropurin and also the production of the intermediate new com pound -8- chlorodiakyl-oxypurin.

Before proceeding with the description it should be stated that the nomenclature herein followed is that adopted by the article'published in Beriohte dc'r Dcutschcn O'hcm-ischen Gesellschaft, Vol. 30, page 549. According to this nomenclature a large number of bodies such as caifein, uric acid, guanin, adenin, &c.are designated by the generic term purins, and their nucleus, the purin group,

has its several carbon and nitrogen atoms numbered in the following manner:

Bearing this nomenclature and system of numbering the position of the atoms in the molecule in mind, the use of terms in the following description willbe readily understood. Thus, for example, the compound xanthin, which may be obtained synthetically by the application of my invention, is styled 2-6- oxy-purin under the new nomenclature,since it has the structural formula:

HNCO

occ r-NH 01; HNGN The two known methyl-trichloropurins described in Bem'chte der Deutschen Chemischen Gesellschaft, Vol. 17, page 331, and Vol. 28, page 2488, have hitherto not been susceptible of conversion into Xanthin derivatives by theaction of alkali, for the reason that the latter causes the chlorin atom in the position 8 to be split off. I have found, however, that the unmethylated trichloropurin, the trichloropurin proper,which, together withits method of preparatiomforms the subject-matter of my Letters Patent of the United States No. 598,502, dated February 8, 1898, behaves. in a radically different manner. This compound is a strong acid and forms stable alkali salts, the formation of the salts resulting in such a modification in the affinities of the three chlorin atoms that on heating With alkali the chlorin atom in the position 6 instead of the chlorin atom in the position 8 is first split off and replaced by oxygen.

At ordinary temperature-For example, when acting upon trichloropnrin with alcoholic alkali at ordinary room temperaturethe former is converted into 6-ethoxy-2-8-dichloropurin having the formula:

GIG O-NH 0 11 .00 O-\TI-I The latter body on treatment with hydrochloric acid loses the two ethyl'groups, forming 2-6-dioXy-8-chl0ropurin, having the structural formula:

0.0 GNH ooi lll/ This latter body, which on account of its structure I term chloro-Xanthin, is by reduction converted into 2-6-dioXy-purin oo CNH II o nN-o-N alcohol methyl-alcohol be substituted for the alcoholic solution, S-chloro-2-6-dimethoxypurin will result. My invention, hence, involves the manufacture of chloro-dialkyl-oxypurins generally and of xanthin therefrom,'directly or indirectly.

In the following detailed description I will first describe the preparation of 8-chloro-2-6- diethoxy-purin by proceeding either from the dichloro-alkyl-oxypurin or from trichloropurim and then the preparation of the xanthin from a chloro-dioxypurin without or with alkyl groups bound to the oxygens in the positions 2 and 6. This description will be preceded by the disclosure of the preparation of dichloro-alkyl-oxypurin, 2-8-dichloro-6-ethoxypurin. The proportions given are all understood to be by weight.

1. Preparation of Q-S-dichZoro-G-ethoxy-purim-Four parts dry trichloropurin, whose properties and mode of preparation are set forth in my aforesaid Patent No. 598,502,

dated February 8, 1898, are dissolved in size teen parts of alcohol, and this solution after being rapidly cooled to about 10 to 15 centigrade, and which as a rule has a tendency to throw out crystals of the trichloropurin, is added to a solution of one and two-tenths parts of sodium in twenty-four parts of alcohol cooled to room temperature. A clear pale yellow liquid results, whose temperature rises spontaneously to about 30 centigrade and soon becomes turbid by reason of a precipitation of sodium-chlorid. The mixture is allowed to stand at ordinary temperature for three hours, whereupon fifty parts of water are added and. the whole is supersaturated slightly with acetic acid. The alcohol is then evaporated off, whereby the dichloro-ethoxypurin is precipitated in colorless very flexible acicular crystals. The same is then purified by recrystallization from hot benzol. Its formula is O H Ol N O, or

N: O. O. (1 H ocl all l ool l N-G-N 2. Preparation of 2-8-dz'chl0ro-6-mc25howg purin.lf in the place of the ethyl-alcoholic solution a methyl-acoholic solution of sodium is employed, the other ingredients and conditions of the above process remaining the same, I obtain 2-S-dichloro-6-methoxy-purin; which melts and decomposes at about 225- centigrade, and which is considerably less soluble in benzene than the ethoxy'compound. l

The generic formula for both of the oxyalkyl-dichloro-purins is:

3. Preparation of 2-6-dielfhosry-S-chloropw Tin from t'r'ichloropm'ma -I heat triohloropu+ rin (one part) together with a concentrated alcoholic solution of, sodium-ethylate (con taining one part of sodium) in a closed vesscl to centigrade, maintaining this temperature for three hours. The sodium-ethylate must be in excess or at least t wo molecules more than sufficient to neutralize the trichloropurin is obtained as a copious precipitate,

which forms fine needles. This new body has the formula C,l-I,,N ,OlO or, structurally expressed N: C. O. 0 H

O H .OC CNI-I l OCI l l 'NCN The reactiontakes place according to the equation:

N:G.Ol

It is very similar in behavior to the monoethoxy compound described under example 1. Like the latter, it softens at about 190 centigrade and melts at about 205, the melting-point being not sharply defined, and fusion being attended by decomposition and evolution of gas. In hot acohol it is very readily soluble, but very diificult of solution in benzol. It is readily soluble in alkalies, including ammonia and baryta-water. Boiling water dissolves the same only with difficulty, one thousand parts of the same being required for the solution of one part of the compound.

4. Preparation of 2-6-dieth0my-8-chloroplarin from 2-8-dichloro-d-ethowy-pzwi-n.The diethoxy compound may also be obtained from the mono-ethoxy-chloro compound by heating the same with excess of sodiu m-ethylate under substantially the same conditions set forth under example 5.

5. Conversion of 8-chlo1'o- -6-dieth000y-pu- 'r'in into xcmthim-The chloro-diethoxy-purin may be converted into xanthin under the infiuence of reducing agents. Thus if the same is dissolved in ten times its weight of hydrogen-iodid or hydriodic acid of the specific gravity 1.96 at ordinary temperature the reduction begins promptly, iodin being liberated. The latter is again reduced by the addition of sufficient phosphonium-iodid or yellow phosphorus. The reduction is completed at the end of about an hour at ordinary temperature. In the course of this reaction the intermediate product 2-6-diethoxypurin is most probably formed, but remains dissolved in the hydrogen-iodid. This diet-hoxypurin, however, already undergoes a further conversion into 2-6-dioxypurin or xanthin in the course of the same reaction, the ethyl radicals being split off by the. strong acid, particularly When dealing with large quantities. This second phase of the reaction is, however, only partial at ordinary temperatures, and consequently only a proportionately small quantity of hydriodate of xanthin is thrown out. If, on the other hand, the whole is subsequently heated on the water-bath, the conversion into xanthin becomes complete and its hydriodate is precipitated in the form of a thick crystalline mass. From this mass the hydriodic acid is evaporated and the residue is treated with dilute aqueous ammonia in slight excess and filtered. The residue is then dissolved in a large quantity of warm aqueous ammonia solution for purification. On boiling or evaporating the ammonia the Xanthin is thrown out in the form of a colorless crystalline powder. The product thus obtained synthetically has all of the properties observed for natural xanthin. The reaction whereby the xanthin is formed under this head takes place according to the equations:

6. Conversion of 8-chlor0- -d-cliethoccypu- Tin into chZ0r0-0ccmthin.lt instead of acting upon the chloro-diethoxypurin with a reduc-. ing agent it is submitted to the influence of hydrochloric acid, the chlorin atom remains To completely. purify, the chloro-xanthin is converted into the readily-crystallizing ammonium salt by dissolving in warm very di lute aqueous ammonia. On slowly cooling the ammonium salt is obtained in the form of small, but well-developed, apparently rectangular tablets. The said ammonium salt is then again decomposed by acid, such as hydrochloric acid, as will be readily understood. S-chloro-xanthin has the composition O H OIN O and the molecular structure:

IIN O 0 O C NH I coi l HN O N It dissolves with difficulty in hot water and alcohol and glacial acetic acid. From the warm solution of its salts it is precipitated by mineral acids as a colorless granular crystal line mass. On heating it chars without melting. It dissolves readily in concentrated sulfuric acid, being precipitated from such solution by the addition of water. Its alkali salts are readily soluble in water. Its potas sium salt crystallizes from strong potash-lye in the form of very fine pliable needles. Its ammonium salt is much less soluble. On slowly cooling of an aqueous solution of the same it crystallizes in small, but well-developed, apparently rectangular tablets.

Ohloro-Xanthin, like xanthin, gives a very strong murexide test. This chloro-dioxypurin is like the chloro-dioxypurin having alkyl combined with the oxygen, such as S-chloro- 2- 6-diethoxypurin, readily converted into Xanthin by the action of a reducing agent, such-as hydrogen-iodid, under substantially the conditions set forth under 5.

The chloroxanthin may, as set forth in my application Serial No. 668,645, be converted into chlorocafi'ein by methylation and the latter by reduction into catfein or 1-3-7t1imethyl-Xant-hin. This mode of obtaining an alkylized Xanthin by methylation and subsequent reduction of, a chloro-oxypurin is, however, claimed generically and specifically in my applications Serial Nos. 668,644 and 668,645, filed concurrently herewith, and is herein only referred to as another illustration of the utility of my compound 8-chloro-2-6- diethoxy-purin.

The present application is designed to cover the preparation of xanthin by the reduction of a chloro-dioxypurin either with or without alkyl groups combined with the oxygen atoms. More specifically my present application covers the 8-chl0ro-2-fi-diethoxy-purin and its mode of preparation, as also the preparation of Xanthin therefrom by reduction.

What I claim, and desire to secure by Letters Patent of the United States, is

1. The process which consists in heating trichloropurin having chlorin' in the places (2), (6) and (8) with an alcoholic alkali.

2. The process which consists in heating trichloropurin with excess of sodium-ethylate.

3. The process which consists in heating trichloropurin with a concentrated alcoholic solution of sodium-ethylate in excess, evaporating the alcohol, dissolving the residue in water and supersaturating the solution with acetic acid.

4. As a new chemical compound, S-chloro- 2-6-diethoxypurin, having the formula above given which trickles at about 190, centigrade, and melts at about 205, centigrade, the fusion being attended by decomposition, which is soluble in hot alcohol, in alkalies, but soluble with difficulty in hot water and benzene and which crystallizes in fine needles.

5. The process of preparing Xanthin which consists in acting on S-chloro-dioxy-purin with a reducing agent.

6. The process of preparing xanthin which consists in submitting 8-chloro-2-6-diethoxypurin to the action of a reducing agent.

7. The process of preparing Xanthin which consists in dissolving S-chloro-2-6-diethoxypurin in hydriodic acid at ordinary temperatures then adding phosphonium-iodid to reduce the liberated iodin, then heating the whole on the water-bath, whereby the hydroiodate of Xanthin is precipitated, then evaporating the hydriodic acid and treating the residue with aqueous ammonia in slight excess.

In testimony. whereof I affix my signature in presence of two witnesses.

EMIL FISCHER.

lVitnesses:

CHAS. H. DAY, HENRY HASPER.

ICC 

